Deregulated expression of the transcription factor, c-Myc, is a common feature of many types of human malignancy. The function of c-Myc remains somewhat elusive, although it has been shown to participate in cell proliferation, apoptosis and metabolism in immortalized cells. Recent studies using primary cells in which c-Myc is overexpressed suggest that c-Myc may actually induce growth arrest. Relatively little is known about the immediate physiologic and molecular consequences of c-Myc overexpression in an organ in vivo. To better understand how c-Myc functions in vivo, we have developed a murine model in which c-Myc is ectopically expressed in the liver. We have shown that transient expression of the human c-MYC transgene results in hepatocyte hypertrophy, which occurs in the absence of significant cell proliferation. This application proposes experiments that will elucidate the mechanisms by which c-Myc increases hepatocyte size. We will determine if the transcriptional properties attributed to c-Myc and the genes it is purported to regulate are preserved in the liver. We will investigate whether c-Myc increases hepatocyte ploidy as a potential mechanism by which c-Myc increases hepatocyte size; these studies will elucidate whether c-Myc causes growth arrest in some hepatocytes, and include a comprehensive evaluation of the effect of ectopic c-Myc on cell cycle regulatory proteins in the liver in wild-type mice and mice deficient in G1/S checkpoint regulators. Finally, we will use this model to identify novel c-Myc target genes that participate in increasing hepatocyte size; or initial studies will evaluate insulin-like growth factor 2 (IGF-2) as a candidate target gene of c-Myc target gene of c-Myc. The results obtained from the experiments using this animal model will allow us to construct new paradigms about how c-Myc functions in vivo.
| Lee, L A; Dang, C V (2006) Myc target transcriptomes. Curr Top Microbiol Immunol 302:145-67 |
| Li, Feng; Xiang, Yan; Potter, James et al. (2006) Conditional deletion of c-myc does not impair liver regeneration. Cancer Res 66:5608-12 |
